Cellular growth and differentiation appear to be initiated, promoted, maintained and regulated by a multiplicity of stimulatory, inhibitory and synergistic factors and hormones. The alteration and/or breakdown of the cellular homeostasis mechanism seems to be a fundamental cause of growth related diseases. Growth modular factors are implicated in a wide variety of pathological and physiological processes including signal transduction, cell communication, growth and development, embryogenesis, immune response, hematopoiesis cell survival and differentiation, inflammation, tissue repair and remodeling, atherosclerosis and cancer.
The transforming growth factor .beta. (TGF-.beta.) family of cytokines/growth factors regulates cell proliferation, differentiation, recognition and death, and figures in the control of development, tissue recycling and repair. Included in this family are Drosophila decapentaplegic (DPP) Sekelsky et al, Proc. Natl. Acad. Sci., USA, 139:1347-1358 (1995)!, TGF.beta.-1, TGF.beta.-2 and TGF.beta.-3; and bone morphogenetic proteins, BMP2/BMP4 Hoodless et al, Cell, 85:489-500 (1996); Graff et al, Cell, 85:479-487 (1996); Liu et al, Nature, 381:620-623 (1996); and Vhang et al, Nature, 383:168-1782 (1996)!.
TGF-.beta. family members signal by simultaneously contacting two transmembrane serine/threonine kinases known as the type I and type II receptors. Certain proteins mediate the complex signalling cascade of the TGF-.beta. family. It has been suggested that different TGF-.beta. family members may signal through different MAD isoforms. MAD (Mothers against DPP) protein was discovered in Drosophila to be required for the signal transduction of DPP. Other MAD proteins in other species, such as Xenopus, mouse, and human, have been found to transduce signaling of BMP2/BMP4.
Several reports suggest that subsequent to ligand activation, the TGF-.beta. type I receptor phosphorylates MAD Hoodless et al, cited above; and Liu et al, cited above!. The phosphorylated MAD then translocates into the nucleus and effects gene expression of selected early intermediate genes specific to the MAD isoform subtype J. Massague, Cell, 85:947-950 (Jun. 28, 1996)!.
Therefore, selective antagonists of the MAD isoforms are anticipated to be beneficial in many diseases where selective interruption of TGF-.beta. or BMP signaling are indicated see, e.g., Eppert et al, Cell, 86:543-552 (Aug. 23, 1996)!. Such disorders include, without limitation, chronic renal failure, scarring, colorectal carcinoma, and cardiovascular disease.
There, thus, exists a need in the art for a variety of TGF-.beta. signalling proteins, antagonists and agonists thereof, as well as compositions and methods for the use of same.